Considering the lengthy history of pharmacological treatment of schizophrenia, the development of novel antipsychotic agents targeting the glutamatergic system is relatively new. A glutamatergic deficit has been proposed to underlie many of the symptoms typically observed in schizophrenia, particularly the negative and cognitive symptoms (which are less likely to respond to current treatments). D-serine is an important coagonist of the glutamate NMDA receptor, and accumulating evidence suggests that D-serine levels and/or activity may be dysfunctional in schizophrenia and that facilitation of D-serine transmission could provide a significant therapeutic breakthrough, especially where conventional treatments have fallen short. A summary of the relevant animal data, as well as genetic studies and clinical trials examining D-serine as an adjunct to standard antipsychotic therapy, is provided in this article. Together, the evidence suggests that research on the next generation of antipsychotic agents should include studies on increasing brain levels of D-serine or mimicking its action on the NMDA receptor.